Process for the recovery of D- or L-{60 -amino-{68 -caprolactam hydrochloride of enhanced optical purity from mixtures of D- and L-{60 -amino-{68 -caprolactam hydrochloride

ABSTRACT

A process for the recovery of D- or L- Alpha -amino- Epsilon caprolactam hydrochloride of enhanced optical purity from a mixture of D- and L- Alpha -amino- Epsilon -caprolactam hydrochloride, which comprises crystallizing out D-or L- Alpha amono- Epsilon -caprolactam hydrochloride from a solution of DAlpha -amino- Epsilon -caprolactam hydrochloride and L- Alpha amino- Epsilon -caprolactam hydrochloride dissolved in a polar solvent, (1) the said solution containing, dissolved therein, at least one of the said D- Alpha -amino- Epsilon -caprolactam hydrochloride and L- Alpha -amino- Epsilon -caprolactam hydrochloride in the super saturated state and (2) the said solution comprising, in addition to the said D- and L- Alpha amino- Epsilon -caprolactam hydrochloride, A. a basic substance having pKb value of not greater than 5 as measured at 29*C. in water or substance having a basicity equivalent thereto, and/or B. a salt of mixture of D- and L- Alpha -amino- Epsilon caprolactam having a solubility in the said polar solvent which is greater than the solubility of D- and L- Alpha -aminoEpsilon -caprolactam hydrochloride in the said polar solvent AND RECOVERING THE CRYSTALLIZED PRODUCT.

United States Patent 1 1 Watase et al.

1 Apr. 22, 1975 1 1 PROCESS FOR THE RECOVERY OF D- ORL-a-AMINO-e-CAPROLACTAM HYDROCHLORIDE OF ENHANCED OPTICAL PURITY FROMMIXTURES OF D- AND L-a-AMINO-e-CAPROLACTAM HYDROCHLORIDE [75] Inventors:Hideo Watase, I-Iino;Yasuhisa Ohno, Hachioji; Tadayoshi Nakamura;Tadashi Okada; Toru Takeshita, Hino, all of J apan 73] Assignee: TeijinLimited, Osaka. Japan 22] Filed: Aug. 22, 1972 21] Appl. No.: 282,667

[30] Foreign Application Priority Data Aug. 27. 1971 Japan... 46-65726Jan. 19. 1972 Japan 47-7525 Jan. 22, 1972 Japan 47-8537 Feb. 14. 1972Japan 47-15474 [52} US. Cl 260/239.3 R [51] Int. Cl C07d 41/06 [58]Field of Search 260/2393 R [56] References Cited UNITED STATES PATENTS3.105.067 9/1963 Nclcmans ct al. 260/2393 R $275,619 9/1966 Brenner ctal. 260/2393 R 3.542.766 11/1970 Ohnogi ct al. 260/2393 R 7/1971Shibahara ct a1. 260/2393 R 3.658.811 4/1972 Tanaka ct al. 260/2393 RPrimary E.\'uminerHenry R. Jiles Assistant Eraminer-Robert T. BondAttorney, Agent. or FirmSherman & Shalloway [57] ABSTRACT A process forthe recovery of D- or L-a-amino-ecaprolactam hydrochloride of enhancedoptical purity from a mixture of D- and L-a-amino-e-caprolactamhydrochloride. which comprises crystallizing out D-orL-a-amono-e-caprolactam hydrochloride from a solution ofD-a-amino-e-caprolactam hydrochloride and L-a-amino-e-caprolactamhydrochloride dissolved in a polar solvent, (1) the said solutioncontaining. dissolved therein. at least one of the saidD-a-amino-ecaprolactam hydrochloride and L-oz-amino-ecaprolactamhydrochloride in the super saturated state and (2) the said solutioncomprising. in addition to the said D- and L-a-amino-e-caprolactamhydrochloride.

A. a basic substance having pKb value of not greater than 5 as measuredat 29C. in water or substance having a basicity equivalent thereto.and/or B. a salt of mixture of D- and L-a-amino-e-caprolactam having asolubility in the said polar solvent which is greater than thesolubility of D- and L-a-amino-e-caprolactam hydrochloride in the saidpolar solvent and recovering the crystallized product.

9 Claims. No Drawings Y practical.

In the latter diastereomer method, an expensive 'opti- PROCESS FOR THERECOVERY OF D- OR L-a-AMINO-e-CAPROLACTAM HYDROCHLORIDE OF ENHANCEDOPTICAL PURITY FROM MIXTURES OF D- AND L-a-AMINO-e-CAPROLACTAMHYDROCHLORIDE This invention relates to a process for the recovery ofD-a-amino-e-caprolactam hydrochloride (D- NI-I CL.HCI) orL-a-amino-e-caprolactam hydrochloride (D-NI-I CLI-ICI) of enhancedoptical purity from a mixture of D-NI-I CLHCI and L-NI-I CLHCI.

In the present specification, by the term a mixture of D- andL-a-amino-e-caprolactam hydrochloride" is meant not only a racemiccompound of D-NI-II CLHCI and L-NH CL.HCl and a racemic mixture of D- NHCL.I-ICl and L-NH CLHCI, but also a molecular or crystalline mixture ofD-NH CL.HCl and L- NH CL.HCI at any mixing ratio. The same definitionapplies to the term D- and L-a-amino-ecaprolactam.

a-Amino-e-caprolactam (NH CL) can be synthesized starting frome-caprolactam or intermediates for its production, which are availablein large quantities and at low costs as materials for the production ofnylon-6 and the like. a-Amino-e-caprolactam is a key compound for theproduction of lysine, and it can be easily hydrolyzed to form lysine.

However, because the compound is normally obtained as a racemic compoundor a racemic mixture of L-a-amino-ecaprolactam andD-a-amino-ecaprolactam (both the racemic compound and the racemicmixture are inclusively called racemic a-aminoe-caprolactam ora-amino-E-caprolactam of the racemic form.), this racemica-amino-e-caprolactam needs to be optically resolved and the resultingoptically active L-a-amino-e-caprolactam nees to be hydrolyzed, in orderto obtain optically active L-lysine monohydrochloride which is valuablefor medicinal uses and as a fortifying agent for human or animal diets.

As the method for the optical resolution of racemica-amino-e-caprolactam, (racemic NH CL), there have been known a seedingmethod comprising converting racemic NH CL to its hydrobromide or its,B-naphthalene-sulfonate. and adding to a solution of the salt a seed ofsuch salt of optical active NH CL, and a method calleddiastreomermethod" (U.S. Pat. No. 3,275,619 and Belgian Pat. No. 696,183). In thefor- 'mer seeding method, expensive hydrobromic acid orB-naphthalenesulfonic acid had to be used, and in order'to obtainvaluable optically active lysine hydrochloride from the hydrobromice orthe B-naphthalenesulfonate of optically active NI-I CL obtained by theoptical resolution, it is necessary to convert the hydrobromide or theB-naphthalenesulfonate to optically active NH CL and separate it afterthe optical resolution, and to convert it to optically active lysine bythe hydrolysis. Accordingly, either from the economical or operationalviewpoint, this method cannot be said to be cal resolving agent needs tobe used and the step of sep' arating the resulting diastereomeric saltinto each constituent is indispensable. If sufticient separation is notaccomplished in the separating step, such diaadvantages as loss of theexpensive resolving agent and reduction of purity of lysine owing toincorporation of the resolving agent in the product result.

Further, a method of recovering NH CLHCI of enhanced optical purity byfractional crystallization or extraction of NH CLHCI of low opticalpurity with the use of water, aqueous ethanol or aqueous methanol hasbeen known (for instance, British Pat. No. 1,256,416). In this method,from a mixture of D- and L-NH CL.HCl containing one optical isomer (L-NHCLl-lCl) in a much greater amount than the other optical isomer (D- NHCL.HCI), NH cLl-lCl of enhanced optical purity containing only theoptical isomer in the excess amount is recovered. Accordingly, in thismethod it is impossible to obtain optically active NH CL.HCI fromracemic NH CL.I-ICl, and use ofa mixture containing one optical isomerin a much greater amount than the other optical isomer is indispensable.Further, the amount of the optical isomer contained in the greateramount and recovered in the state having enhanced optical purity fromsuch mixture is at most an amount corresponding to the differencebetween the total amount of said optical isomer contained in the greateramount in the starting mixture and the amount necessary for forming amixture of equal parts of both the optical isomers. Still further, ifthe recovery ratio is heightened to a level approximating such maximumamount, the optical purity of the product is much reduced. These aredefects and disadvantages of the above known method. Hence, this methodcannot constitute an optical resolution.

It is therefore a primary object of this invention to provide a processfor separating and recovering easily and economically D-NH CL.HCl and/orL-NH CL.HCI of enhanced optical purity from a mixture containing D-NHCL.HCI and L-NH CL.HCl at any mixing ratio without employing anyparticular optical resolving agent.

Another object of this invention is to provide a process for separatingand recovering L-NH CL.HCl and- /or D-NH CL.HCl from racemic NH CLHCI.

Still another object of this invention is to provide a process forseparating and recovering from a mixture containing D-NH CL.HCI and L-NHCL.HCl at an optional ratio, the optical isomer contained in a greateramount in the state having enhanced optical purity, in an amountexceeding the amount corresponding to the difference between the totalamount of said optical isomer contained in the greater amount in thestarting mixture and the amount necessary for formation of a mixture ofequal parts of both the optical isomers, namely in such a great amountthat in the mother liquor left after the recovery of the optical activeNH CLHCI, the other optical isomer contained in a smaller amount in thestarting mixture is present in turn in an excessive amount.

A further object of this invention is to provide a process in which D-NHCL.HCl and L-NH CL.I-ICI of enhanced optical purity are separated andrecovered successively from a mixture containing these optical isomersat any mixing ratio, thereby to obtain both D- NI-I CLHCI and L -NHCL.HCl of enhanced optical purity in the form separated from each other.

I Other objects and advantages of this invention will be apparentfrorn'the description given hereinbelow.

" The above objects and advantages of this invention can be attained bya process for the recovery of D- or L-aamino-e-caprolactam hydrochlorideof enhanced optical purity from a mixture of D- andL-a-amino-ecaprolactam hydrochloride, which comprises crystallizing outD- or L-a-amino-e-caprolactam hydrochloride from a solution ofD-a-amino-e-caprolactam hydrochloride and L-a-amino-e-caprolactamhydrochloride dissolved in a polar solvent, (1) the said solutioncontaining dissolved therein, at least one of the said D-a'amino-e-caprolactam hydrochloride and L-a-amino-ecaprolactamhydrochloride in the supersaturated state and (2) the said solutioncomprising, in addition to the said D- and L-a-amino-e-caprolactamhydrochloride,

A. a basic substance having a ,,l(,, value of not greater than 5 asmeasured at 25C. in water or a substance having a basicity equivalentthereto, and/or B. a salt of a mixture of D- and L-a-amino-ecaprolactamhaving a greater solubility in the said polar solvent than D- andL-a-amino-ecaprolactam hydrochloride; and recovering the crystallizedproduct.

This invention will now be illustrated in more detail.

STARTING MATERIAL Mixtures containing D-a-amino-e-caprolactamhydrochloride (D-NH CL.HCl) and L-a-amino-ecaprolactam hydrochloride(L-NH CLHCI) at any mixing ratio may be used in this invention.

As the method for synthesis of Nl-l CL, there are known many methodsincluding those in which e-caprolactam or intermediates for itsproduction such as cyclohexanol, chlorocyclohexane, etc., are used asstarting materials (see, for example, U.S. Pat. No. 3,052,670 and GermanPat. No. 1,955,038). NH CL synthesized by such a method takes always aracemic form (D,L-NH CL) containing equal parts of D- and A mixturecontaining either of D-NH CL and L- NH CL in excess may be obtained byincorporating D- NH CL or L-NH CL into racemic D,L-NH CL synthesized bysuch a method, or is obtained in the form of the residue left after apart of D-Nl-l CL or L-NH CL is separated from racemic D,L-NH CL by theoptical resolution.

Such mixture of D'NHgCL and L-NH CL may be converted to a mixture of D-and L-oz-amino-ecaprolactam hydrochloride, to which the definition hasbeen given hereinabove, by dissolving the mixture of D-NH CL and L-NH CLin a suitable solvent such as water, a lower alcohol, e.g., methanol,and an aqueous solution thereof, and blowing into the solution anequimolar amount or slightly excessive amount of hydrogen chloride.

SOLVENT In this invention, this mixture containing D- NH CL.HCl and L-NHCL.HCl at any mixing ratio is dissolved in a polar solvent to form asolution in which at least one of D-NH CL.HCl and L-NH CLHCl isdissolved in the supersaturated state.

Any polar solvent being unreactive with D- NH CLHCI and L-NHgCL.HCl andcapable of dissolving them therein may be used in this invention. Thereason for the use of a polar solvent in this invention is that D-Nl-lCL.HCl and L-NH CLHCl are, in general, insoluble or hardly soluble innon-polar solvents. Even if D- and L-NH CL.HCl is dissolved in anon-polar solvent, its solubility is very low.

Of the polar solvents, one exhibiting a high dissolving power for D- andL-Nl-l CLJ-ICl and being economical is preferred.

As such preferred polar solvents there may be mentioned, for instance,(i) water, (ii) monoto tri-hydric aliphatic alcohols, (iii) ketones,(iv) aliphatic carboxylic acids and lower alkyl esters thereof, (v) N-unsubstituted amides and N-alkyl-substituted amides, (vi) sulfoxides,(vii) cyclic ethers, (viii) aliphatic nitriles, and (ix) mixtures of atleast two selected from (i) to (viii) above.

More preferred examples of such polar solvents are as follows:

(i) Water:

Ordinary water for industrial use may be employed advantageously.

(ii) Monoto tri-hydric aliphatic alcohols:

In general, mono-, diand tri-hydric alcohols having 1 to 6 carbon atomsare preferably used. For instance, monohydric alcohols such as methanol,ethanol, npropanol, isopropanol n-butanol, sec-butanol, isobutanol,tert-butanol, n-pentanol, methyl cellosolve and ethyl cellosolve,dihydric alcohols such as ethyleneglycol, trimethyleneglycol,tetramethyleneglycol, diethyleneglycol and glycerine monomethyl ether,and trihydric alcohol such as glycerine and trimethylolpropane arepreferably employed.

(iii) Ketones:

Of ketones, aliphatic ketones having up to 6 carbon atoms are preferred.Specific examples of such preferred ketones are acetone,methylethylketone, methylisopropylketone and methylisobutylketone.

(iv) Aliphatic carboxylic acids and their lower alkyl esters:

Use of aliphatic carboxylic acids having up to 10 carbon atoms such asaliphatic monocarboxylic acids, e.g,, formic acid, acetic acid,n-propionic acid, isopropionic acid, n-butyric acid, iso-butyric acidand sec-butyric acid is preferred. Also halogen-substituted carboxylicacids such as monochloroacetic acid, dichloroacetic acid andtrichloroacetic acid are preferably used. Still further, lower alkylesters of carboxylic acids such as mentioned above, for instance, methylacetate, ethyl acetate and methyl propionate are preferably used.

(v) N-unsubstituted amides and N-alkyl-substituted amides:

Of N-unsubstituted amides, formamide and acetamide are preferred, and asN-alkyl-substituted amides are preferably used, for instance,dimethylformamide, dimethylacetamide, N-methyl-apyrrolidone andhexamethylphosphorylamide.

(vi) Sulfoxides:

Dimethylsulfoxide, diethylsulfoxide, methylethylsulfoxide and the likeare used preferably as sulfoxides.

(vii) Cyclic ethers:

l,4-Dioxane, 1,3-dioxane, tetrahydrofuran and the like are suitable ascyclic ethers.

(viii) Aliphatic nitriles:

Preferable aliphatic nitriles include acetonitrile, propionitrile,butyronitrile and the like.

(ix) Mixtures of at least two of (i) to (viii) above;

Any combination of at least two of the above polar solvents (i) to (vii)at any mixing ratio may be used in the form of a mixed solvent. Mixedsolvents consisting of at least two polar solvents selected frommethanol, ethanol, ethyleneglycol, glycerine, acetone, acetic acid,dimethylformamide, dimethylsulfoxide, l,4-dioxane, acetonitrile and thelike, and mixed solvents consisting of water and at least one polarsolvent selected from those exemplified above, are preferably used.

In this invention, a solution in which a racemic mixture ofa-amino-e-caprolactam hydrochloride is dissolved in such polar solventin the supersaturated state, or a solution in which a mixture ofa-amino-ecaprolactam containing either of L-NH CL.HCl and D-Nh CL.HCl ina greater amount than the other optical isomer is dissolved in the polarsolvent such that at least one of L-NH CLHCl and D-NH CL.HCl isdissolved in the supersaturated state, is used. In short, D- NH CL.HCland L-Nl-l cLHCl are dissolved in the polar solvent such that at leastone of the two optical isomers is dissolved in the supersaturated state.

ADDITIVE In this invention, at least one compound selected from (A) asubstance having a ,,l(,, value of not greater than 5 as measured at25C. in water or a substance having a basicity equivalent theeto and (B)and a salt of a mixture of D- and L-a-amino-e-caprolactam having asolubility in the polar solvent which is greater than the solubility inthe polar solvent of D- and L-a-aminoe-caprolactam hydrochloride, isalso dissolved as an additive in the polar solvent, while D-NH CLHCI andL- Nl-l CLHCl are dissolved in the polar solvent such that at least oneof them is dissolved in the supersaturated state.

As additive (A), there may be preferably used, for example, (i)aliphatic amines, (ii) alicyclic amines, (iii) heterocyclic amines, (iv)alkali metal hydroxides and (v) alkaline earth metal hydroxides.Specific examples of such basic substances are as follows.

(i) Aliphatic amines:

There may be exemplified methylamine, ethylamine, n-propylamine,isopropylamine, n-butylamine, tertbutylamine, sec-butylamine,n-amylamine, isoamylamine, n-hexylamine, n-pentylamine, noctylamine,dimethylamine, diethylamine, di-npropylamine, di-isopropylamine.di-n-butylamine, ditert-butylamine, di-sec-butylamine, di-n-amylamine,trimethylamine, triethylamine, tri-n-propylamine, tri-nbutylamine,ethylenediamine, propylenediamine, trimethyenediamine,tetramethylenediamine, pentamethylenediamine, hexamethylenediamine,diethylenetriamine, triethylenetetramine, allylamine, monoethanolamine,diethanolamine, triethanolamine, benzylamine, dibenzylamine,B-phenylethylamine, omethylbenzylamine, tetramethyl ammonium hydroxide,tetra-n-butyl ammonium hydroxide and tetraethyl ammonium hydroxide.

(ii) Alicyclic amines:

As alicyclic amines, there may be mentioned, for example,cyclopentylamine, cyclohexylamine, dicyclopentylamine, dicyclohexylamineand tricyclohexylamine.

(iii) Heterocyclic amines:

As heterocyclic amines, there may be mentioned, for instance,pyrrolidine, piperidine, Z-methylpiperidine, piperazine,a-amino-ecaprolactam, a-aminolaurylolactam, melam and melem.

(iv) Alkali metal hydroxides:

There may be exemplified lithium hydroxide, sodium hydroxide, potassiumhydroxide, rubidium hydroxide and cesium hydroxide. Of these, lithiumhydroxide, sodium hydroxide and potassium hydroxide are especiallypreferably used.

(v) Alkaline earth metal hydroxides:

As alkaline earth metal hydroxides, there may be mentioned, for example,magnesium hydroxide, calcium hydroxide and barium hydroxide.

In addition to the above basic substances (i) to (v), there may beemployed such compounds as sodium methoxide, potassium methoxide, sodiumethoxide, potassium ethoxide, sodium propoxide, potassium propoxide,sodium butoxide, potassium butoxide, sodium formate, potassium formate,sodium acetate, potassium acetate, sodium propionate, potassiumpropionate, sodium benzoate, potassium benzoate, sodium salicylate,potassium salicylate, sodium succinate, potassium succinate, sodiumadipate, potassium adipate, ammonia and guanidine.

Not only salts of a racemic mixture of a-amino-ecaprolactam, but alsosalts of any mixture of L-NH CL and D-NH CL may be used as additive (B),as long as they have a greater solubility in the polar solvent to beused than D and L-NH CLHCI.

As such Salts are used preferably (vi) carboxylic acid salts, (vii)carbonates and (viii) sulfates of mixtures of L-NH CL and D-NH CL.

Examples of the carboxylic acid salt (vi) include salts of monobasicaliphatic carboxylic acids having 1 to 4 carbon atoms such as formicacid, acetic acid, propionic acid and butyric acid, salts of monobasicaromatic carboxylic acids such as benzoic acid and salicyclic acid,dibasic acids having 2 to 6 carbon atoms such as oxalic acid, malonicacid, succinic acid, citric acid, glutaric acid and adipic acid,hydroxycarboxylic acids such as glycolic acid, lactic acid and tartaricacid, and amino acids such as glutamic acid and aspartic acid.

Any of salts of the carboxylic acids such as exemplified above may beused as the additive (B), as long as its solubility in the polar solventto be used is greater than the solubility of D- and L-NH CLHCI in thepolar solvent.

As the additive to be used according to this invention, a mixture ofL-Nl-l CL and D-NH CL, especially a racemic mixture of D,L-NH CL, andits monobasic carboxylate, its carbonate or its sulfate are particularlypreferred.

It is preferred that the basic substance (A), expecially the mixture ofL-NH CL and D-NH CL, or the salt of the D- and L-NH CL mixture (B) ispresent in the state dissolved in the polar solvent in an amount of atleast 0.2 mole, especially at least 0.5 mole, per mole of the D,L-NHCL.HCl mixture dissolved in the polar solvent. The amount of theadditive to be made present in the state dissolved in the polar solventmay be within such a range that the additive can be dissolved in thepolar solvent and that at least one optical isomer of D- NH CLHCI andL-NH CL.HCL is dissolved in the polar solvent and the supersaturateddissolution state of the one optical isomer can be maintained.Accordingly, the upper limit of the amount of the additive added variesdepending on the kind of the additive and the kind of the polar solvent.For instance, when the optical resolution of racemic D,L-NH CL.HCl iseffected with the use of racemic D,L-Nh CL and an aqueous solution of amonohydric alcohol having a water content of less than 50 percent (forexample, aqueous methanol), better results are obtained by making theracemic D,L-Nh CL present in the dissolved state in an amount of, forexample, about l0 moles or less, preferably about 8 moles or less, permole of the racemic D,L-NH CL.I-ICI.

When aliphatic, alicyclic and heterocyclic amines other than D,L-NH CL,or alkali metal and alkaline earth metal hydroxides are added anddissolved as the additive (A), most of these basic substances catch theHCl of D- and/or L-NH CLHCI dissolved in the supersaturated soltuion,thereby to form D- and/or L-NH CL in the polar solvent. In such cases, asimilar effect to that obtained when a mixture of D- and L-NH CL isadded and dissolved as the additive is sometimes manifested.

However, when such basic substances are made present in the dissolvedstate, the amount of D- and L- NI-I CLHCI is decreased by the formationof D- and L-NI-I CL and hence, in some cases, it becomes impossible tomaintain the supersaturated dissolution state of D- and/or L-NI-I-CLHCI. In such cases, care must be taken so as to maintain thesupersaturated dissolution state of D- and/or L-NI-I CLHCI in the polarsolvent by either further adding D- and L'NHzHCl mixture, limiting theamount of the additive added, supplying hydrogen chloride into thesolution, or adjusting the solution temperature appropriately.

As compared with the cases where the optical resolution is carred outwithout the additive of this invention, the optical resolution processaccording to this invention makes it possible to separate and recover L-NH CL.HCI or D-NH CLHCl of more enhanced optical purity from a mixtureof D- and L-NI-I CLHCI as illustrated in the Examples given below.Furthermore, when one of the optical isomers of the same optical purityis to be recovered, it is possible according to this invention to obtaina much greater amount of the desired optical isomer than in the casewhere no additive is used.

As regards the reason why such effects are attained by the additive ofthis invention, we consider that the presence of the additive in thedissolved state may be effective for maintaining the supersaturateddissolution state of D- and/or L-NH CL.HCI more stably, and that in casea mixture of D- and L-NI I CL as mentioned in (A) above, or a saltthereof as mentioned in (B) above, is used as the additive, as comparedwith the case where such additive is not used, the additive may exhibitan activity to suppress effectively the crystallization of thehydrochloride of the undesired optical isomer (e.g. D-NHgCL-HCI). Thiscrystallization is likely to be brought about by the increase of therelative concentration of said optical isomer in the solution caused bythe progress of the crystallization hydrochloride of the intendedoptical isomer (e.g. L-NH CLHCl).

In order to prepare the above-mentioned solution of polar solvent to beused in this invention, in which (I) a mixture of D- and L-NH CLHCI isdissolved so that at least one of said optical isomers is dissolved inthe supersaturated state and (2) at least one additive selected fromadditives (A) and (B) is made present in the dissolved state, a suitableamount of D- and L- NH CLHCI as mentioned in (1) above is dissolved atfirst in a suitable polar solvent, if necessary, under heating, and thesupersaturated state of D-NH CL.HCI and- /or L-NH CLHCI is attained by asuitable treatment such as cooling, concentration or variation in thesolutioh composition. Then a prescribed amount of the additive is addedto the solution while maintaining the supersaturated state. It is alsopossible to adopt a method comprising dissolving in advance the additivein the polar solvent, adding and dissolving the mixture of D- and L-NI-ICL.I-ICI as mentioned in (1) above into such solution, and attaining thesupersaturated state by a suitable treatment such as mentioned above.

In case it is made difficult to maintain the supersaturated state of D-or L-NI-I CL.HCI by the addition of the additive, as mentioned above,the superstaturated state can be maintained conveniently by adding freshD- and L-NH CLHCI or I-ICl, or by conducting a suitable treatment suchas cooling or concentration of the solution.

On the preparation of such supersaturated solutions, some additivescatch the HCl of the D- and L- NH CL.I-ICI dissolved in the polarsolvent and they precipitate in the form of the hydrochloride. In suchcase, the supersaturated state may be attained by separating suchprecipitated hydrochloride prior to the preparation of thesupersaturated solution and then effecting, for instance, concentrationor cooling. In case the precipitated hydrochloride can readily beseparated from the resulting L- or D-Nl-I CL.I-ICl of enhanced opticalpurity, the crystallization of L- or D-NH CL.-HCI or enhanced opticalpurity may be carried out without preliminary separation of theprecipitated hydrochloride of the additive from the supersaturatedsolution.

CRYSTALLIZATION OF D- OR L-NI-I CLHCI Either of the following twomethods may be adpoted to crystallize D-Nl'l CLHCl or L-NH CLI-ICI ofenhanced optical purity out of the prepared solution of polar solvent inwhich at least one of D-NH CL.HCI and L-NI-I CL.HCl is dissolved in thesupersaturated state and at least one member selected from the additivesas mentioned above is made present in the dissolved state (which will bereferred to merely as supersaturated solution hereinbelow).

Method 1 In the case of fractional crystallization of D- or L- NH CLHClof enhanced optical purity from the supersaturated solution in whichequal parts of D- NH CLHCI and L-NH CL.I-ICI are dissolved, seedingneeds to be effected. A small amount of an optical isomer the same asthe intended isomer to be recovered is added to the supersaturatedsolution as a seed. The seed is desireably in the crystal form having anoptical purity as high as possible. The amount of the seed is notparticularly critical. Satisfactory results can be usually attained byadding the seed in an amount of about I to 10 percent by weight based onthe amount of D,L- NH CL.HCl dissolved in the supersaturated solution.

Method 2 In the case of fractional crystallization of D- or L- NH CL.HCIof enhanced optical purity from the supersaturated solution in which oneof the optical isomers is dissolved in a greater amount, the saidoptical isomer contained in a greater amount is naturally crystallizedout from the supersaturated solution and the naturally crystallizedcrystals act as the seed. Therefore, it is not particularly necessary toeffect seeding. However, in order to accomplish the resolutioneffectively in a short period of time and to obtain D- or L-NH CLHCl ofmuch enhanced optical purity, it is preferred to add an optical isomerthe same as that dissolved in a greater amount as a seed.

In each of these methods l) and (2), L-Nl-l CL.HCl is selectivelyprecipitated as crystals with high selectivity from the supersaturatedsolution seeded with L- NH CLHCl, and similarly. D-NH CL.HCl isprecipitated as crystals from the supersaturated solution seeded withD-NH CLHCl. Needless to say, the optical isomer contained in excess tothe other and dissolved in the supersaturated state is crystallized outin the natural crystallization of the method (2).

As a result of our research, it has been found that crystals of each ofL-NH CL.HCl and D-NHgCL-HCl take the forms of both B-type crystals andy-type crystals. The sapce distance and diffraction intensity of each ofthese ,B-type and y-type crystals determined by X-ray diffractionanalysis are shown in the following Table 1.

Table l X-Ray Diffraction Spectrum Analysis of D-or LNH CL.HCl

Notes to Table l:

1. The diffraction intensity was evaluated according to the scale ratedbelow:

VS very strong S strong M medium W weak VW very weak 2. The measurementwas conducted with the use of an X-ray diffraction meter of the modelD-3F manufac tured by Rigaku Denki K. K. (Japan) under the followingconditions:

Measurement temperature: room temperature Slit width: No.2 1, No. 3 1,No.4 0.4 mm

Scanning rate: l/mm Chart speed; 1 cm/min It has been found that whencrystals of L-NH cLHCl or D-NH CLl-lCl having a crystal structure of the,B-type are added to the supersaturated solution as the seed, L-NHCL.HCl or D-NH CbHCl of much enhanced optical purity can be obtained inmuch better yields from the supersaturated solution. Accordingly, it

a is preferred that 62 -type crystals of L-NH CL.HCI or D-NH CLHCl areused as seed crystals for crystallization.

In this invention, the seeding need not be always effected afterformation of the supersaturated solution. For instance, it is possibleto adopt a method comprising adding seed crystals of D-NH CLHCI or L- NHCL.HCl to a solution in which at least one of D- NH CLHCI and L-NHCL.HCl is saturated, and then attaining the supersaturated state in atleast one of D- NH CLHCl and L-NH CbHCl. The short, it is suffi' cientin this invention that at the time of crystallizing out D- or LNH CL.HClof enhanced optical purity the supersaturation is attained in thesolution.

When the solution is maintained in the supersaturated state,precipitation of crystals of D- or L- NH- CLHCI is allowed to begin. Thedecrease of the solution concentration brought about with the process ofprecipitation of the crystals is to be compensated by conducting any ofthe above-mentioned procedures adopted for preparation of thesupersaturated solution, for instance, by cooling, and crystallizationcan be further continued. Agitation of the solution is effective forconducting the crystallization operation smoothly, and especially whenthe supersaturated solution has a high viscosity, agitation is veryeffective.

Precipitated crystals can be separated by a customary solid-liquidseparating procedure, for instance, filtration or centrifugalseparation. If necessary, the separated crystals are washed with a smallamount of water or a solvent such as methanol and ethanol to remove thesolvent attached to the crystals or the additive added for increasingthe crystallization electivity. Thus, optically activea-amino-e-caprolactam hydrochloride of enhanced optical purity can beobtained. Since the additive attached to the crystals has a highersolubility in such a washing solvent than a-amino-e-caprolactamhydrochloride, it can readily be removed from the crystals together withthe washing solvent in the state dissolved therein.

The mother liquor left after the one optical isomer of enhanced opticalpurity (e.g., L-NH CLHCl of enhanced optical purity) has been thuscrystallized out, is then converted to an supersaturated solution againby adding afresh a starting mixture of D,L-NH CL.HCI, or is merely leftalone, and the crystallization is repeated by optionally adding the seedof the other optical isomer (e.g., D-NH CL.HCI). Thus, there areobtained crystals of the optical isomer (e.g., D-NH CL.HCl) having anoptical activity contrary to that of the isomer (e.g., L-NH CL.HCl)previously crystallized out in the form of the hydrochloride. Thus, whenthe above crystallization operation is repeated while keeping a goodbalance among the amount of precipitated crystals, the amount of thestarting mixture to be supplied afresh and the amount of seed crystals,the starting mixture of D,L-NH CL.HCl can be optically resolvedcontinuously to obtain alternately L-NH CLHCl of enhanced optical purityand D-NH CL.HCI of enhanced optical purity.

The intended optical isomer of optically active a-amino-e-caprolactamhydrochloride so obtained can be converted to optically active lysine orits salt by conducting the hydrolysis according to a customary method.For instance, L-NH CLHCI can readily be hydrolyzed when it is treatedunder heating with a molar excess of hydrochloric acid, and L-lysinedihydrochloride can be obtained. When the resulting L-lysinedihydrochloride is dissolved in methanol and D- and/orL-aamino-e-caprolactam is added to the solution, L-lysinemonohydrochloride is quantitatively precipitated, while the D- and/orL-a-amino-e-caprolactam remains in the form of the hydrochloride in thesolution to which is has been added. Therefore. if a mixture of D,L-NH-Cl is added for the precipitation of L-lysine monohydrochloride, themixture remains in the solution. Accordingly, this mixture can be usedas the starting material for the optical resolution process of thisinvention as it is or after it has been separated from the solution.

Further, L-NH- CLHCl, for instance, can be converted to L-lysinemonohydrochloride by treating it with sulfuric acid, thus hydrolyzing itto L-lysine monohydrochloride sulfate and then treating it with calciumhydroxide [Ca(OH) to convert it into L-lysine mono hydrochloride andcalcium sulfate [CaSO The non-intended optically active isomer ofa-aminoe-caprolactam hydrochloride, for instance, D- NH CLHCl, issubjected to racemization according to a customary method, and theresulting racemic compound can be forwarded to the optical resolutionstep. Accordingly, in this invention racemic a-amino-ecaprolactamhydrochloride can be used as the starting material for the opticalresolution and all of it can be converted to valuable, optically activelysine monohydrochloride. On the contrary, in the conventional recoverymethod as disclosed in British Pat. No. 1,256,416, racemica-amino-e-caprolactam hydrochloride cannot be used as the startingmaterial and not all of it can be converted to optically active lysinemonohydrochloride.

As compared with the conventional seeding method using hydrobromide or,B-naphthalene-sulfonate as described hereinbefore, the process of thisinvention is advantageous in that it is possible to accomplish moreeasily the optical resolution of D,L-a-amino-ecaprolactam while using itin a cheaper form, i.e., in the hydrochloride form, and since theoptically active a-amino-e-caprolactam can be obtained in the form ofthe hydrochloride, it can be directly hydrolyzed to valuable, opticallyactive lysine hydrochloride. Further, the process of this invention isadvantageous over the above-mentioned conventional diastreomer method inthat such troublesome operations as separating the resulting salt of theoptically active a-amino-ecaprolactam and a resolving agent intorespective compounds need not be conducted and the optical resolutioncan be accomplished by much simpler procedures.

As is seen from the foregoing description, the optical resolutionprocess of this invention has various advantages over the conventionalresolution methods, especially in preparing L-lysine hydrochloride.

Effects and advantages attained by the process of this invention willnow be illustrated more specifically. When the results of Example 1 andComparative Example 1 given below are, for instance, compared with eachother, it is seen that even under such conditions as will provideL-a-amino-e-caprolactam hydrochliride of an optical purity of only 86percent if the optical resolution of a racemic mixture of D,L-NH CL.HClis effected in the absence of D,L -amino-e-caprolactam,La-amino-e-caprolactam hydrochloride of an optical purity of 100 percentcan be obtained if the opticalresolution is effected in the presence ofD,La-amino-ecaprolactam in accordance with the process of thisinvention. The values of the resolution efficiency in both cases arecompared with respect to the amounts of L- NH CLHCI obtained (i.e., thevalues (as=bXc-s) obtained by reducing the amount L-NH CL.HCl seeded (s)from the amount of L-NH CLHCI calculated (a) by multiplying the amountof crystallized a-amino'e-caprolactam hydrochloride (b) by the opticalpurity thereof (c). The value obtained of L-NH HCl is 0.44 g in the casethat D,L'waminoe-caprolactam is absent, whereas the value obtained ofL-NH CL.HCI is 0.70 g in the case that D,L-a-amino-e-caprolactam isadded. This improvement of the resolution efficiency means that whena-amino-e-caprolactam hydrochloride is crystallized at the samecrystallization yield, the hydrochloride of an optical purity ofIOO'percent can be obtained very easily when D,L-NH CL is made presentand that when the hydrochloride of a similar optical purity iscrystallized out, the presence of D,L- HN CL can enhance greatly thecrystallization yield and give a much higher yield.

Such excellent effects as are attained by using D,L-aamino-e-caprolactamas the additive are similarly observed with respect toD,L-a-amino-e-caprolactam acetate or sulfate or other basic substances(A) to be used in this invention (see, for instance, Examples 15 and16). Accordingly, it is apparent that the process of this invention,which is characterized in that D,L-a-aminoe-caprolactam, its salts (B)or the above-mentioned basic substances (A) are added in the dissolvedstate in the optical resolution of a racemic mixture of D,L-amino-e-caprolactam or a mixture of D-a-amino-ecaprolactam andL-a-amino-e-caprolactam, exhibits excellent effects and can be practisedwith great industrial advantages.

This invention will now be illustrated in more detail by reference toExamples and Comparative Examples, in which the optical purity of-amino-e-caprolactam hydrochloride is the value of the L-NH CL.HCl or D-NH CL.HCl content (percent) calculated from the optical rotation asmeasured on a l-N hydrochloric acid solution of the product.

In Examples and Comparative Examples, the following abbreviations areused:

DLNH CL.HCI: D,L-a-amino-e-caprolactam hydrochloride The abbreviatedidentification of the crystallizing conditions given in the Tables, forinstance, 40 30 means that the crystallization is effected by coolingthe solution from 40 to 30C. over a period of 20 minutes.

EXAMPLE 1 10.0g of D,L-a-amino-e-caprolactam hydrochloride (opticalpurity; 50 percent) and 20.0g of D,L-a-aminoe-caprolactam were dissolvedunder heating into 34.0 g of a mixed solvent of ethyleneglycol and water(EG/ H O weight ratio 4/1 The solution was maintained at 40C. forminutes under agitation, and then 1.50 g of L-a-amino-e-caprolactamhydrochloride was added to the solution to effect seeding.Simultaneously with the seeding, cooling of the solution was initiated,and it was cooled to C. over a period of 20 minutes, following whichprecipitated crystals were separated by filtration. The crystals werewashed with 10 g of ethanol and dried to obtain 2.20 g ofL-a-amino-ecaprolactam hydrochloride having [MD of 25.7 (C=3.0; l-Nhydrochloric acid solution) and an optical purity of 100 percent. Thus,the amount of the L- NH CLl-lCl actually obtained was 0.70g (the valueobtained by reducing the amount of the seed (1.50 g) COMPARATIVEEXAMPLES 2 and 3 In the same manner as in Comparative Example 1, theoptical resolution was carried out by varying the amount of the solventand the amount of the seed crystals as indicated in Table 2. Results ofthese comparative experiments as well as those of Comparative Examfromthe recovered amount). 20 P l are also Show" Table Table 2 Opti-Starting Material Basic Solvent Seed call Substance C rystal- Crystallizcd active Additive lization Product product Kind amo- Kind amo-Kind amount Kind amo- Condi- Kind Amount (g) um um um tions (Opticalpurity Yield Ex. (g) (g) (g) (g) (g) 1 DLNH CL.HC1 DLNH CL EG/H O=4 LNH-,CL.HC1 20 L-NH CL.HC1

4 DLNH CL.HC1 DLNH CL EGIH O=4 L-NH CL.HC1 20 LNH CL.HC1

*1 DL-NH CL.HCl EGIH O=4 LNH CL.HCl 20 LNH Cl.HCl

*2 DLNH CL.HCl EGIH O=4 i LNH CL.HCI 18 LNH C1.HC1

Comparative EXAMPLES 2 to 9 EXAMPLE 10 COMPARATlVE EXAMPLE 1 Opticalresolution of D,L-a-amino-e-caprolactam hydrochloride was carried out inthe same manner as in Example 1 except that only 10.0 g ofD,L-a-amino-e- 40.0g of D,L-a-amino-e-caprolactam hydrochloride wasdissolved in 138.0 g of a mixed solvent of nbutylamine and methanol(n-BuNH /.MeOH weight ratio 18/120) under heating.

The solution was maintained at 40C. for 20 minutes under agitation, andthen 1.0g of L-a-amino-ecaprolactam hydrochloride was added to thesolution as the seed. Simultaneously with the seeding, cooling of thesolution was initiated. The solution was cooled to 22C. over a period of30 minutes, and precipitated crystals were collected by filtration.

The recovered crystals were washed with a small quantity of ethanol anddried to obtain 1.52 g of L-aamino-e-caprolactam hydrochloride having anoptical purity of 99 percent ([0]D =25.2, C=3, l-N hydrochloric acid).

EXAMPLE 29 10.0 g of D,L-a-amino-e-caprolactam hydrochloride and 10.0 gof D,L-oz-amino-e-caprolactam acetate were dissolved in 46.0 g of amixed solvent of ethyleneglycol EXAMPLE 38 d water liq/H O i h ratio 2under heating 5 10.0 g of D,L-a-amino-e-caprolactam hydrochloride Thesolution was maintained at 400C. for 10 minand g of p were utes, and 0.1g of L-a-amino-e-caprolactam hydrochlo- Solved under heating into g of aride was added as the seed to the solution. Simultaneously with theseeding, cooling of the solution was lnitiated, and the solution wascooled to 30C. over a 10 l d f 1 period of 13 minutes. Precipitatedcrystals were recov- The so p Wds mamtdme at 4 or O mlnums ered byfiltration, washed with 10 gof cooled methanol under agmmon and h g of Da-amln9'' and dried to obtain 0.64 g of L a amin0 capmlactam caprolactamhydrochloride was added to the solution. hydrochloride having an opticalpurity of 86 percent.

EXAMPLES 30 to 37 In the Same manner as n Exampl the optical res-Simultaneously with the seeding, cooling of the soluolution ofD,L-a-amino-e-caprolactam hydrochloride tion as the seed was initiatedand the solution was coolwas carried out by employing a salt ofD,L-a-amino-eed to 255C. over a period of 20 minutes. Precipitatedcaprolactam as indicated in Table 4 instead of D,L-acrystals wererecovered by filtration, washed with g amino-e-caprolactam acetate.Conditions and results of ethanol and dried to obtain 2.48 g ofD-a-amino-eare shown in Table 4, where the results of Example 29caprolactam hydrochloride having [a]D of 22.2 are also illustrated. andan optical purity of 93 percent.

Table 4 1) Starting Basic Substance Crystal- Material Additive SolventSeed lization Kind Amount Kind Amount Kind Amount Kind Amount condi- (g)(g) (g) (g) tions Example 29 DLNH CL.HCI l0.0 DL NH. C- 10.0 EG/H O=446.0 L NH,CL.l-lcl 0.l l3

L.AcOH to-ml Example 30 DLNH CL.HCl l0.0 DLNH2CL.H- 18.0 EGIHZO=4 43.0LNH2CL.HCI 0.1 I5

Example 31 DLNH CL.HCl l0.0 DLNH2C- 15.0 Me0H/' 50.0 LNH CL.HCl 0.l

LACOH H 0=4 39 -+32 Example 32 DL-NH CL.HCl l0.0 DLNH2CL.H- 15.0 MeOHl-50.0 LNH CL.HCl 0.1 20

COOH H o=4 40 Example 33 DLNH CL.HCl 10.0 DLNH2CL.P- l5.0 EGIHZO=4 55.0LNH CL.HCl 0.] l8

rCOOH to- 30 Example 34 DLNH CL.HCl l0.0 DLNH2CL.H- 20.0 EGIH2O=4 32.0LNH CL.HCl 0.l l6

Example 35 DLNH2CL.HCI l0.0 DLNH2CL 20.0 EG/H O=4 34.0 LNH CL.l-lCl 0.l20

L-Lys.HCl 2.0 31 Example 36 DL-NH CL.HCl l0.0 DLNH2CL 20.0 EGIHEO=4 34.0LNH CL.HCl 0.l l8

LLys.HCl 2.0 40-32 Example 37 DLNH CL.HCI 10.0 DLNH .CL 50.0 H O 18.0L-NH,CL.HC| 1.0 20

LLys.HCl l0.0 40 23 Table 4 (2) EXAMPLES 39 TO 71 AND COMPARATIVEEXAMPLES 8 TO 10 crystallized Product Optical Amoumlg) 32? 1n the samemanner as in Example 38, the optical resolution ofD,L-a-amino-e-caprolactam hydrochloride Example 29 L-NH CL.HCl 0.64 86lvent as indicated in Example 30 L-NHZCLHCl 0.6l 88 was Carved out byemploymg a so d Example 31 L N c c Q60 85 Table 5 instead of the watersolvent. Condltlons an reg i zg 84 sults are shown in Table 5, where theresults of Examxampe L-NHZ L.HC| 0.70 82 Example 34 L NH2CL HC1 Q79 80ple 38 are also given. As comparative examples, the op Example 35L-NH,,CL.HCI 1.22 91 tlcal resolutlon was also carried out in theabsence of Example 36 L-NH CL.HCI 0.83 97 3 f ch com Example 37 292 99an added basic substance. The results 0 u p tive experiments are alsoshown in Tables 5 and 6.

Table 6 (3) Starting Material Basic Substance Additive Solvent Seed Crystal- Kind Amount Kind Amount Kind Amount Kind Amount lization (g) (g)(g) (g) Condition Example 64 Dl.NH:Cl..H(l 10.0 Dl.-NH. .C1. 10.0 (jly/H()=7/3 30.0 l.NH Cl..HCl 0.1

40 3h Example 65 DLNH Cl..HCl 10.0 Dl.NH- ,(l. 20.0 H2O/DMF=55/45 23.0LNH. .C1..HC| 1.0

' 40 3Z Example 66 Dl.NH Cl..HC1 10.0 Dl.NH. .C1. 30.0 DMF/H:()=l7/582.0 l.NH Cl.HC1 1.0 15

10- 2 Example 07 Dl.NH (1..HCl 10.0 D1. NH,C1. 30.0 DMF/H. .()=3/2 23.0LNH. .CL.H(1 1.0 10

lo- 33 Example 68 DLNH. 10.0 Dl.NH. .Cl. 50.0 Mc()H/DMF=7/3 73.0 L-NH-,CL.HCI 1.0 20

CL.HC1 ll-+30 Example 69 D1.NH. .(1..H(1 1.0 D1.NH. .(1 3.0 DMso/H. ,o=32 2.3 l.NH. .C1..H(| 0.1 3

"sh- 31 Example 70 Dl.-NH ('l..HCl 1.0 Dl.NH. ,Cl. 3.0 Dioxz1nc/H ()=3/24.0 l.NH. .Cl..HCl 0.1 10

1 28 Example 71 Dl.NH (l..HCl 1.0 Dl.-NH. .('1. 3.0 AcN/H .()=3/2 3.0l.NH. ,Cl..HCl 0.1 10

40- 3s Comparative D1.NH:(1..HCl 1.0 F.(; 49.0 LNH. .CL.HC1 0.1 114Example X 411-30 Comparative Dl.NH Cl..HCl 1.0 EG/H. ,()4 55.0 l.-NHCl..HCl 0.1 30 Example 9 40 34 Comparative Dl.NH Cl..H(l 1.0 Gl '/H-()=7/3 32.0 l.NH Cl..HCl 0.1 15 Example 10 40- 36 Ta l 6 ing racemic D,L-NH CLHCI is used as the starting material for the next cycle of theoptical resolution. C rystallizcd product Kind Amount (g) Optical Purity("/11 EXAMPLE 73 .-a-"-e-' Example 64 L NHLCLIHCI 0'53 89 46 0 g of D Lamino caprolactam hydrt chlor1de Example 65 2'35 88 4 g ofL-a-ammo-e-caprolactam hydrochlonde and 250 Example 66 l.-NH CL.H(l 1.9693 g of D,L-a-amino-e-caprolactam were dissolved in 280 P' 72 g ofmethanol under heating. The solution was main- Example 68 L'NH2CL.H(l2.05 100 d I C f 10 d d Example 69 lrNHzCLHCI Q39 72 tame at or minutesun er ag1a1on, an Example 70 LNH- -Cl.HCl 0.16 98 then 5.0 g ofL-a-amino-e-caprolactam hydrochloride Example 35 was added to thesolution to effect seeding. Simulta- 2x53? z ncously with the seeding,cooling of the solution was Comparative L-NH CL.HCl 0.52 87 initiated,and the solution was cooled to 30C. over a E p 2 period of 20 minutes,Precipitated crystals were recovomparatrvc a Example 10 L NH2Cl Hc| Q 8]4 ered by filtration (the filtrate is designated as mother 0 liquor 1The recovered crystals were washed w1th 20 ml of methanol and dried toobtain 15.02 g of L-aamino-s-caprolactam hydrochloride having an opticalEXAMPLE 72 purity of 100 percent. Accordingly, the amount of L- 4 Thefiltrate left after removal of prec1p1tated As is seen from the resultsof this Example. in accordance with the process of this invention,alternate crystallization procedures of crystallizing out the L-isomerat first and then crystallizing out the D-isomer can be conductedrepeatedly and very effectively, and therefore, L-NH CLHCl and D-NHCLHCl can be prepared with great industrial advantages. ln case onlyindustrially valuable L-NH CLHCl is wanted, D- NH CL.HCl obtained by theabove optical resolution procedures is subjected to racemization and theresult- NH CLHCI actually obtained by the optical resolution 5 was 6.02g.

Then, 12.0 g of D,L-a-amino-e-caprolactam hydrochloride was added afreshand dissolved into the mother liquor 1 under heating. The solution wasmaintained at 40C. for 10 minutes under agitation, and then 3.0 g ofD-a-amino-e-caprolactam hydrochloride was added as the seed to thesolution. Simultaneously with the seeding, cooling of the solution wasinitiated and the solution was cooled to 30C. over a period of 20minutes. Precipitated crystals were recovered by filtration (thefiltrate is designated as mother liquor 2"). The crystals were washedwith 20 ml of methanol and dried to obtain 15.05 g ofD-a-amino-e-caprolactam hydrochloride having an optical purity ofpercent. Accordingly, the amount of D-NH CL.HCl actually obtained by theoptical resolution was 12.05 g.

The mother liquor 2 was treated in the same manner as described above,and the mother liquor 3 left after removal of precipitated crystals wasalso similarly treated. These procedures were repeated. All the resultsare shown in Table 7.

As is seen from the results of this Example, in accordance with theprocess of this invention, L-NH CLHCI 23 of an optical purity of 100percent and D-NH- CLHCI of an optical purity of 100 percent can beobtained alternately from a mixture of L-NH CLHCI and D- NH CL.HCl in acontinuous manner. Therefore, if the A. a basic substance having a Kvalue of not greater than 5 as measured at 25C. in water or a substancehaving a basicity equivalent thereto, said substance being selected fromthe group consisting of aliprocess of this invention is practised incombination 5 phatic amines having not more than 12 carbon atowith theracemization step, only L-NH CL.HCl or only ms; aryl lower alkyl amines;alicyclic amines having D-NH CLHCI can be obtained with great industrialnot more than 6 carbom atoms in the ring; pyrroliadvantages startingfrom a mixture of L-ot-amino-e dine; piperidine; Z-methyl-piperidine,piperazine; caprolactam hydrochloride and D-a-amino-e-(reminds-caprolactam; a-amino-laurylolactam; caprolactam hydrochloride.l melam; melem; alkali metal hydroxides; alkaline Table 7 (1) OpticalStarting Material Basic Substance Solvent Seed Crystal- Resolutionlization Amount Amount Amount Amount Condition Kind (g) Kind (g1 Kind(g) Kind (g) First DLNH CLHCl 46.0 DLNHZCL 250 Methanol 280 LNH2CL.HCI5.0 20 Operation LNH- CL.HC| 4.0 40 30 Second Mother Liquor l DNH2CL.HCI3.0 20 Operation DL-NH CLHC'l l2.0 40-)30 Third Mother Liquor 2 12.0 LNHCL.HCl 3.0 20 Operation DL 40 30 Forth Mother Liquor 3 I20 D-NH CL.HCl3.0 20 Operation DLNH iCLHCI 40-) 30 Fifth Mother Liquor 4 12.0 LNHCL.HCl 3.0 20 Operation DLNH CL.HCl 40 30 Sixth Mother Liquor 5 l2.()D-NH2CL.HCI 3.0 Operation DLNH CL.HCl 40 Table 7 2 earth metalhydroxides; tetra-lower alkyl ammo-' nium hydroxides; alkali metal loweralkoxides; al- Crysmmzed product Optically Active 30 kali metal salts ofmonobasic lower aliphatic acids, Product alkali metal salt of benzoicacid; alkali metal salt of KM i gzr' g C Amount obtained (g) salicyclicacid; alkali metal salt of dibasic aliphatic acids having 4-6 carbonatoms; ammonia and LNH2CL.HCI 15.02 6.02 guanidine and (100 D NH2CL4HC|15,05 12,05 B. a salt of a mlxture of D- and L-wamino-e 1 ,001 H OIcaprolactam having a solubility in the said polar L NH1CL'HC' 6% solventwhich is greater than the solubility of D- D-NH CL.HCl 15.03 12.03 andL-a-amino-e-caprolactam hydrochloride in the L NH2CL'HC] 1259 said polarsolvent, said salt being selected from the (100) 40 group consisting ofsalts of a monobasic aliphatic D 14-9! 11-91 carboxylic acid having l-4carbon atoms; a monobasic aryl carboxylic acid, a dibasic loweraliphatic acid having 2-6 carbon atoms; a hydroxylated dibasic aliphaticacid having 2-6 carbon atoms; and an amino acid having not more than 4carbon atoms, with D-NH CL or L-NH Cl, or a mixture What we claim is:thereof;

1. A process for the recovery of D- or L-a-amino-em an amount of atleast 0.2 mole per mole of the total caprolactam hydrochloride ofenhanced optical purity amounts of D- and L-a-amino-e-caprolactamhydrofrom a mixture of D- and L-a-amino-e-caprolactam by chloride andwithin such a range that the additive can drochloride dissolved in apolar solvent selected from be dissolved in the polar solvent and thatat least one the group consisting of water, monoto tri-hydric aliopticalisomer of D-NH ClHCl and L-NH CLHCI is phatic alcohols having less than7 carbon atoms; alidissolved in the polar solvent and the supersaturatedphatic ketones having less than 7 carbon atoms; alidissolution state ofthe one optical isomer can be mainphatic carboxylic acids having lessthan 11 carbon tained, crystallizing the one optical isomer dissolved inatoms and the lower alkyl esters thereof; N- said solution at thesupersaturated state and recovering unsubstituted and N-substitutedamides having less the crystallized product. than 7 carbon atoms; loweralkyl sulfoxides having less I 2. The process of claim 1, wherein thepolar solvent than 5 carbon atoms; cyclic ethers having less than 5contains, dissolved therein, racemic a-amino-ecarbon atoms; aliphaticnitriles having less than 5 carcaprolactam hydrochloride in thesupersaturated state. bon atoms; and mixtures thereof, the said solutioncon- 3. The process of claim 1, wherein the polar solvent taining (1),dissolved therein, at least one of the said Contams, i l d herein,a-amino-l68 -caprolactam D-a-amino-e-caprolactam hydrochloride and L-hydrochloride in the supersaturated state, the said amino-e-caprolactarnhydrochloride in the supersatui no--caprolactam hydrochloride comprisingone rated state d (2), i ddi i t th id D- d L- optical isomer in anamount greater than the amount of amino-e-caprolactam hydrochloride, anadditive selected from at least one of the group consisting essentiallyof the other optical isomer.

4. The process of claim 1, wherein the basic substance having a ,,K,,value of not greater than 5 as measured at 25C. in water is a mixture ofD-a-amino-- caprolactam and L-a-amino-e-caprolactam.

5. The process of claim 1, wherein the basic substance having a ,,l(,,value of not greater than as mea sured at 250C. in water is racemicoz-amino-ecaprolactam.

6. The process of claim 1, wherein the basic sub stance having a ,,K,,value of not greater than 5 as measured at 25C. in water is a memberselected from the group consisting of aliphatic amines. alicyclicamines, heterocyclic amines, alkali metal hydroxides and alkaline earthmetal hydroxides.

7. The process of claim 1, wherein the salt of a mixture of D- andL-a-amino-e-caprolactam having a solu bility in the said polar solventwhich is greater than the caprolactam hydrochloride.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 13,879,382 DATED April 22 1975 INVENTOR(S) HIDEO WATASE, ET AL.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Claim 1, line 28 thereof: cancel "carbom" and substitute carbon Claim 1,line 34 thereof: after "acids" cancel and substitute Claim 3, line 2thereof: cancel -amino-168-capro1actam" and substituteOt-amino-icaprolactam Claim 5, line 2 thereof: cancel "Sas" andsubstitute 5 as Signed and sealed this 24th day of June 1375.

{SEAL} Attest:

C. lZARSI-ZALL DAB-3N RUTH 115x303 Commissioner of Patents attestingOfficer and Trademarks

1. A PROCESS FOR THE RECOVERY OF D- OR L-AMINO-ECAPROLACTAMHYDROCHLORIDE OF ENHANCED OPTICAL PURITY FROM A MIXTURE OF D-ANDL-A-AMINO-E-CARPROLACTAM HYDROCHLORIDE DISSOLVED IN A POLAR SOLVENTSELECTED FROM THE GROUP CONSISTING OF WATER, MONO- TO TRI-HYDRICALIPHATIC ALCOHOLS HAVING LESS THAN 7 CARBON ATOMS, ALIPHATIC KETONESHAVING LESS THAN 7 CARBON ATOMS, ALIPHATIC CARBOXYLIC ACIDS HAVING LESSTHAN 11 CARBON ATOMS AND THE LOWER ALKYL ESTERS THEREOF, NUNSUBSTITUTEDAND N-SUBSTITUTED AMIDES HAVING LESS THAN 7 CARBON ATOMS, LOWER ALKYLSULFOXIDES HAVING LESS THAN 5 CARBON ATOMS, CYCLIC ETHERS HAVING LESSTHAN 5 CARBON ATOMS, ALIPHATIC NITRILES HAVING LESS THAN 5 CARBON ATOMS,AND MIXTURES THEREOF, THE SAID SOLUTION CONTAINING (1), DISSOLVEDTHEREIN, AT LEAST ONE OF THE SAID D-A-AMINO-E-CAPROLACTAM HYDROCHLORIDEAND L-AAMINO-E-CAPROCLATAM HYDROCHLORIDE IN THE SUPERSATURATEDCAPROLACTAM HYDROCHLORIDE, AN ADDITIVE SELECTED FROM AT LEAST ONE OF THEGROUP CONSISTING ESSENTIALLY OF A. A BASIC SUBSTANCE HAVING A PKB VALUEOF NOT GREATER THAN 5 AS MEASURED AT 25*C. IN WATER OR A SUBSTANCEHAVING A BASICITY EQUIVALENT THERETO, SAID SUBSTANCE BEING SELECTED FROMTHE GROUP CONSISTING OF ALIPHATIC AMINES HAVING NOT MORE THAN 12 CARBONATOMS, ARYL LOWER ALKYL AMINES, ALICYCLIC AMINES HAVING NOT MORE THAN 6CARBON ATOMS IN THE RING, PYRROLIDINE, PIPERIDINE, 2-METHYL-PIPERIDINE,PIPERAZINE, A-AMINO-E-CAPROLACTAM, A-AMINOLAURYLOCTAM, MELAM, MELAM,ALKALI METAL HYDROXIDES, ALKALINE EARTH METAL HYDROXIDES, TETRA-LOWERALKYL AMMONIUM HYDROXIDES, ALKALI METAL LOWER ALKOXIDES, ALKALI METALSALT OF BENZOIC ACID, ALKALI METAL SALT OF SALICYCLIC ACID, ALKALI METALSALT OF DIBASIC ALIPHATIC ACIDS, HAVING 4-6 CARBON ATOMS, AMMONIA ANDGUANIDINE, AND B. A SALT OF A MIXTURE OF D-AND L-A-AMINO-E-CAPROLACTAMHAVING A SOLUBILITY IN THE SAID POLAR SOLVENT WHICH IS GREATER THAN THESOLUBILITY OF D-AND L-AMINO-E CAPROLACTAM HYDROCHLORIDE IN THE SAIDPOLAR SOLVENT, SAID SALT BEING SELECTED FROM THE GROUP CONSISTING OFSALTS OF A MONOBASIC ALIPHATIC CARBOXYLIC ACID HAVING 1-4 CARBON ATOMS,A MONOBASIC ARYL CARBOXYLIC ACID, A DIBASIC LOWER ALIPHATIC ACID HAVING2-6 CARBON ATOMS, A HYDROXYLATED DIBASIC ALIPHATIC ACID HAVING 2-6CARBON ATOMS, AND AN AMINO ACID HAVING NOT MORE THAN 4 CARBON ATOMS,WITH D-NH2CL OR L-NH3CL, OR A MIXTURE THEREOF, IN AN AMOUNT OF AT LEAST0.5 MOLE PER MOLE OF THE TOTAL AMOUNTS OF D-AND L-A-AMINO-E-CAPROLACTAMHYDROCHLORIDE AND WITHIN SUCH A RANGE THAT THE ADDITIVE CAN BE DISSOLVEDIN THE POLAR SOLVENT AND THAT AT LEAST ONE OPTICAL ISOMER OF D-NH2CL.HCIAND L-NH2CL.HCL IS DISSOLVED IN THE POLAR SOLVENT AND THE SUPERSATURATEDDISSOLUTION STATE OF THE ONE OPTICAL ISOMER CAN BE MAINTAINED,CRYSTALLIZING THE ONE OPTICAL ISOMER DISSOLVED IN SAID SOLUTION AT THESUPERSATURATED STATE AND RECOVERING THE CRYSTALLIZED PRODUCT.
 1. Aprocess for the recovery of D- or L- Alpha -amino- epsilon -caprolactamhydrochloride of enhanced optical purity from a mixture of D- and L-Alpha -amino- epsilon -caprolactam hydrochloride dissolved in a polarsolvent selected from the group consisting of water, mono- to tri-hydricaliphatic alcohols having less than 7 carbon atoms; aliphatic ketoneshaving less than 7 carbon atoms; aliphatic carboxylic acids having lessthan 11 carbon atoms and the lower alkyl esters thereof; N-unsubstitutedand N-substituted amides having less than 7 carbon atoms; lower alkylsulfoxides having less than 5 carbon atoms; cyclic ethers having lessthan 5 carbon atoms; aliphatic nitriles having less than 5 carbon atoms;and mixtures thereof, the said solution containing (1), dissolvedtherein, at least one of the said D- Alpha -amino- epsilon -caprolactamhydrochloride and L-Alpha -amino- epsilon -caprolactam hydrochloride inthe supersaturated state and (2), in addition to the said D- and L-Alpha-amino- epsilon -caprolactam hydrochloride, an additive selected from atleast one of the group consisting essentially of A. a basic substancehaving a pKb value of not greater than 5 as measured at 25*C. in wateror a substance having a basicity equivalent thereto, said substancebeing selected from the group consisting of aliphatic amines having notmore than 12 carbon atoms; aryl lower alkyl amines; alicyclic amineshaving not more than 6 carbom atoms in the ring; pyrrolidine;piperidine; 2-methyl-piperidine, piperazine; Alpha -amino- epsilon-caprolactam; Alpha -amino-laurylolactam; melam; melem; alkali metalhydroxides; alkaline earth metal hydroxides; tetra-lower alkyl ammoniumhydroxides; alkali metal lower alkoxides; alkali metal salts ofmonobasic lower aliphatic acids, alkali metal salt of benzoic acid;alkali metal salt of salicyclic acid; alkali metal salt of dibasicaliphatic acids having 4-6 carbon atoms; ammonia and guanidine, and B. asalt of a mixture of D- and L- Alpha -amino- epsilon -caprolactam havinga solubility in the said polar solvent which is greater than thesolubility of D- and L- Alpha -amino-epsilon -caprolactam hydrochloridEin the said polar solvent, said salt being selected from the groupconsisting of salts of a monobasic aliphatic carboxylic acid having 1-4carbon atoms; a monobasic aryl carboxylic acid; a dibasic loweraliphatic acid having 2-6 carbon atoms; a hydroxylated dibasic aliphaticacid having 2-6 carbon atoms; and an amino acid having not more than 4carbon atoms, with D-NH2CL or L-NH2Cl, or a mixture thereof; in anamount of at least 0.2 mole per mole of the total amounts of D- and L-Alpha -amino- epsilon -caprolactam hydrochloride and within such a rangethat the additive can be dissolved in the polar solvent and that atleast one optical isomer of D-NH2Cl.HCl and L-NH2Cl.HCl is dissolved inthe polar solvent and the supersaturated dissolution state of the oneoptical isomer can be maintained, crystallizing the one optical isomerdissolved in said solution at the supersaturated state and recoveringthe crystallized product.
 2. The process of claim 1, wherein the polarsolvent contains, dissolved therein, racemic Alpha -amino- epsilon-caprolactam hydrochloride in the supersaturated state.
 3. The processof claim 1, wherein the polar solvent contains, dissolved therein, Alpha-amino-168 -caprolactam - hydrochloride in the supersaturated state, thesaid Alpha -amino- epsilon -caprolactam hydrochloride comprising oneoptical isomer in an amount greater than the amount of the other opticalisomer.
 4. The process of claim 1, wherein the basic substance having apKb value of not greater than 5 as measured at 25*C. in water is amixture of D- Alpha -amino- epsilon -caprolactam and L- Alpha -amino-epsilon -caprolactam.
 5. The process of claim 1, wherein the basicsubstance having a pKb value of not greater than 5as measured at 250*C.in water is racemic Alpha -amino- epsilon -caprolactam.
 6. The processof claim 1, wherein the basic substance having a pKb value of notgreater than 5 as measured at 25*C. in water is a member selected fromthe group consisting of aliphatic amines, alicyclic amines, heterocyclicamines, alkali metal hydroxides and alkaline earth metal hydroxides. 7.The process of claim 1, wherein the salt of a mixture of D-and L- Alpha-amino- epsilon -caprolactam having a solubility in the said polarsolvent which is greater than the solubility of D-and L- Alpha -amino-epsilon -caprolactam hydrochloride in the said polar solvent is at leastone member selected from organic carboxylic acid salts, carbonate andsulfate of a mixture of D-and L- Alpha -amino- epsilon -caprolactam. 8.The process of claim 7, wherein the salt of a mixture of D-and L- Alpha-amino- epsilon -caprolactam is at least one member selected from thegroup consisting of formate, acetate, propionate, and butyrate of amixture of D- and L- Alpha -amino-epsilon -caprolactam.